Heterocyclic amino phenoxyacetic esters; acid addition salts, and quaternary ammonium salts thereof



United States Patent HETEROCYCLIC A MINO PHENOXYACETIC ESTERS; ACIDADDITION SALTS, AND ggATERNARY AMMONIUM SALTS THERE- Seymour L. Shapiro,deceased, late of Hastings on Hudson, N.Y., by Florence M. Shapiro,executrix, Hastings on Hudson, N.Y., and Louis Freedman, Bronxville, andHarold Soloway, New Rochelle, N.Y., assignors to U. S. Vitamin &Pharmaceutical Corporation, New York, N.Y., a corporation of New York NoDrawing. Original application Feb. 18, 1963, Ser. No. 259,460, nowPatent No. 3,218,328, dated Nov. 16, 1965. Divided and this applicationJuly 23, 1965, Ser. No. 489,773

4 Claims. (Cl. 260-2943) This application is a continuation-impart ofUS. application Serial No. 818,548, filed June 8, 1959, now abandoned,and a division of application Serial No. 259,460, iiled February 18,1963, now U-S. Patent No. 3,218,328, patented November 16, 1965.

This invention relates to heterocyclic amino substituted phenoxyaceticacid compounds in which the heterocyclic amino group is attached to thephenyl ring through a ring nitrogen atom, and includes correlatedimprovements and discoveries whereby novel compounds having usefulcharacteristics are provided.

A principal object of this invention is to provide novel heterocyclicamino substituted phenoxyacetic acid compounds, including the acids,esters, amides, salts, acid addition salts and quaternary ammoniumsalts.

Another object of the invention is to provide compositions which areparticularly effective for reducing the cholesterol level of blood,containing heterocyclic amino substituted phenoxyacetic acid compounds,esters, amides and related compounds.

In accordance with this invention, it has been determined thatphenoxyacetic acid compounds having a heterocyclic amine group attachedto the phenyl nucleus through a ring nitrogen atom are particularlyeffective as hypocholo-esteremic agents. The heterocyclic amine grouppreferably contains at least about four carbon 3,270,025 Patented August30, 1966 In the above formula, R can be hydrogen or a lower alkyl grouphaving from 1 to 6 carbon atoms, R can be selected from the groupconsisting of hydroxy, lower alkoxy, cycloalk-oxy preferably having from5 to 7 carbon atoms, hydrazino, monoand dilower alkyl-hydrazino, aminoof the formula and lower oxyalkyl amino of the formula of nitrogen,oxygen and sulfur, at least one being nitrogen,

the remaining ring atoms being carbon. The ring atoms can beunsubstituted or substituted with inert groups such as lower alkyl,hydroxy and carbonyl or keto oxygen, =0. The total number of carbonatoms in the group N Z preferably does not exceed about 15.

atoms and may also contain other hete-rocyclic substitu- I ents, such asnitrogen, oxygen and sulfur, either as part of the ring or attached toother atoms which are part of the ring. Preferably the heterocyclicamine group has from four to ten atoms in the ring, of which from one tothree, preferably one, should be heterocyclic atoms, the remainder beingcarbon atoms. The heterocyclic amine group can be substituted in anyposition on the phenyl nucleus, ortho, meta or para to the oxyaceticacid group.

The alpha carbon atom of the acetic acid group attached through anoxygen atom to the phenyl nucleus can be substituted or unsubstituted.If substituted, it is preferably substituted with a lower alkyl grouphaving from 1 to 6 carbon atoms.

Suitable heterocyclic amino phenoxyacetic acid compounds of thisinvention are the phenoxyacetic acids and the esters and amides of thephenoxyacetic acids with lower alkyl alcohols, cycloalkyl alcohols,lower alk'anolamines, ammonia and lower alkyl amines.

The phenoxyace-tic acid compounds of this invention can be defined bythe following formula:

It will be evident from the foregoing that the phenoxyacetic acidcompounds of the invention are acids when R is OH, esters when R isalkoxy or cycloalkoxy or oxyalkylene, and amides when R is amino. Theterm acid compound is used generically herein to refer to all of thesesubgenera of the invention.

Thus, in the foregoing formula, R R and R, can each be, for example,hydrogen, methyl, ethyl, n-propyl, isopropyl, n butyl, iso-butyl,t-butyl and any of the pentyl and hexyl isomers. R can, for example, behydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, nsbutoxy, isobutoxy,t-hutoxy and any of the isomeric pentoxy and hexoxy derivatives,cyclopent-oxy, cyclohexoxy and cycloheptoxy, amino, monomethylamino,dimethylamino,

' monoethylamino, diethylamino, rnonoisopropylamino, di-

hydrazino, hydrazyl,

methyl hydrazyl, ethyl hydrazyl, propyl and Thus N Z can be, for exampleCHzCH:

in which the Q groups are alkylene groups containing from one to aboutten carbon atoms, n is zero or one and the total number of ring atoms inthe group N Z ranges from about four to about ten. Representative N Zorb-011F011,

om-om-on,

oH -om-orr,

The following compounds \are illustrative of compounds coming within thescope of the invention CHa-CE:

CH CH CHy-C H] CHz-CHg it H The acetate ester thus obtained can behydrolyzed to form the acid, can be transesterified with an alcohol ofthe formula R OH to form the appropriate ester, can be reacted to formamides with ammonia and with primary or secondary amines and withhydrazines. In an alternative procedure, the compounds of this inventioncan be prepared by condensing a nitrophenol with an ethyl-alphahaloalkanoate, reducing the resultant nitrophenoxy acetate to theaminophenoxy acetate and cyclizing the amino group to form aheterocyclic group. Reduction and ring closure can take place eitherprior to or after esterification or amide formation. An equation forthis preparation is as follows:

with further procedure as in Preparation I.

An alternative method of preparing the heteroaminophenols which can beused in Preparation I consists of ring closure with ortho, meta or paraanisidine followed by cleavage of the ether with hydriodic acid. Thisprocedure can be illustrated as follows:

(III) (a) O C H: O C H:

The resultant compounds can be reacted with any pharmaceuticallyacceptable inorganic or organic acid to form non-toxic pharmacologicallyacceptable acid addition salts such as hydrochlorides, hydrobromides,nitrates, sulfates, phosphates, acetates, formates, tartrates, malates,theophyllinates, 8-chloroetheophyllinates, and the like. Similarly,through the use of selected quaternizing agents, such as alkyl sulfatesand alkyl halides, e.g., methyl iodide, ethyl bromide, methylp-toluene-sulfonate, allyl bromide, ethyl bromacetate, and the like,non-toxic pharmacologically acceptable quaternary salts of the novelcompounds are readily prepared.

These quaternary salts can be represented by the formula I n O-CH-C-Rawherein R is selected from the group consisting of hydrogen and anorganic radical having from one to eight carbon atoms such as methyl,ethyl, propyl, butyl, octyl, allyl, pentyl, benzyl and carboethoxyalkylsuch as carboethoxymethyl, and A is an inert non-toxic pharmacologicallyacceptable anion, such as bromide, iodide, chloride andp-toluenesulfonate.

When R contains a nitrogen atom, the quaternary salt can be formed atthat nitrogen atom or at both the R nitrogen atom and the heterocyclicnitrogen atom.

The quaternary ammonium salts can be prepared by conventional methods asby refluxing equivalent quantities of the appropriate amino substitutedphenoxyacetic acid with an alkyl halide or an alkyl sulfate in an inertsolvent such as ethanol or benzene. The quaternary ammonium saltsgenerally crystallize out on standing. Where crystallization does notoccur, the solution can be cooled or an additional hydrocarbon solventsuch as hexane can be added in accordance with conventional techniques.Where the double quaternary salt is desired, two equivalents of thealkyl halide or alkyl or alkyl sulfate can be added.

The acid addition salts are prepared by reacting equivalent quantitiesof the amino substituted phenoxyacetic acid and the desired acid in aninert solvent such as ethanol or benzene and recovering the acidaddition salt by conventional means.

The following working examples illustrate the best modes of preparingthe compounds of this invention.

Example I A mixture of 102 g. (0.84 mole) of o-anisidine, g. (0.84 mole)of 1,4-dibromobutane, 172 g. (1.12 mole) of sodium carbonate and 900mls. of acetonitrile were refluxed with stirring for 34 hours. Afterfiltering off the salts, the solution was evaporated down and theresidue taken up in dilute hydrochloric acid. The solution was washedwith ether, then made basic with dilute sodium hydroxide and theresulting oil extracted into three portions of ether. These werecombined, dried over anhydrous magnesium sulfate, then filtered, thesolvent evaporated off and the residue distilled to give 103 g. ofo-(1-pyrrolidinyl)anisole, boiling at 127130 at 5 mm. gm. of theo-(1-pyrrolidiny1)anisole so prepared and 50 ml. of constant boilinghydriodic acid were refluxed together for 28 hours, permitting methyliodide to distill out as formed. At the end of this time, the hydriodicacid was removed at diminished pressure leaving a clear, thick oil. Thiswas dissolved in water, the solution made basic with a saturated,aqueous solution of sodium bicarbonate and the resulting precipitatefiltered off to yield o-(l-pyrrolidinyl phenol), melting at 109- 111.21.2 g. (0.13 mole) of this o-(l-pyrrolidinyl) phenol, 21.8 g. (0.13mole) of ethyl bromoacetate, 18.5 g. (0.13 mole) of potassium carbonateand 200 ml. of acetone were refluxed with stirring for 40 hours. Thesolids were then filtered off, the filtrate evaporated down to a thickoil and this oil dissolved in benzene. This solution was extracted withseveral portions of dilute hydrochloric acid, and the resulting aqueoussolution made basic again with 40% aqueous sodium hydroxide to yield anoil which was taken up in ether. The ethereal solution was then driedover anhydrous magnesium sulfate, the drying agent filtered off, theether removed and the residue distilled to give 2.6 g. ofethyl-a-[o-(l-pyrrolidinyl)phenoxy]acetate, boiling at 136-139" C. at0.25 mm. 11 1.5465.

Anal.-Calc. for C14H19NO3: C, H, N, Found C. 67.2; H, 7.6; N, 5.3.

Example II 3-dimethylaminopropylamine (7.5 g., 0.075 mole), 3.8 g.(0.015 mole) of ethyl-a-[o-(1-pynrolidinyl)phenoxy] acetate and 10 dropsof methanolic sodium methylate were heated in an oil bath at 140 C. fora total of 17 hours. From time to time, the bath was raised to 160 C. todistill out the ethanol formed. After cooling, pentane was added to thereaction mixture and a small quantity of insoluble material filteredoff. The pentane filtrate was then evaporated down with the excess3-dimethylaminopropylamine being distilled off. The product remainingwhich boiled at 178-182 C. at 0.005 mm. (n =1.5474), was identified asa-[o-(l-pyrrolidinyl phenoxy] -N- 3-dimethylaminopropyl) acetamide.

Example III A solution of 33.4 g. (0.2 m.) of ethyl bromoacetate in 50mls. of acetone was slowly added to a stirred mixture of 27.4 g. (0.2m.) of m-nitrophenol, 27.6 g. anhydrous potassium carbonate and 150 mls.of acetone. After refluxing and stirring for 7 hours, the solid wasfiltered off, solvent evaporated off from the filtrate and the residuedistilled to give 41.9 g. (93%) of ethyl 2-(rnnitrophenoxy)acetate. Asolution of 41.9 g. (0.19 In.) of the ethyl Z-(m-nitrophenoxy)acetate in208 mls. of ethanol with 0.3 g. of platinum oxide was hydrogenated in aParr Hydrogenator at an initial pressure of 3 atmospheres. Hydrogenuptake was complete (105%) after 70 minutes of shaking. After removalfrom the hydrogenator and filtration, the solvent was removed atdiminished pressure, the residue taken up in dry ether and treated withdry hydrogen chloride. Filtration yielded 38 g. melting at 125-135Recrystallization from acetonitrile gave 33 g. of ethylZ-(m-aminophenoxy)acetate hydrochloride. A mixture of 8.0 g. (0.034 m.)of the ethyl 2-(m-aminophenoxy)acetate hydrochloride and 5.4 g. (0.051m.) of anhydrous sodium carbonate and rnls. of acetonitrile was addedwhile a solution of 7.4 g. (0.034 m.) of 1,4-dibromobutane in 20 mls. ofacetonitrile was slowly added. Stirring was continued while refluxingfor 27 hours. Filtration, removal of solvent and distillation gave 5.9g. (70%) of product, boiling at 150-154 at 0.2 mm. The distillatesolidified slowly 14- on cooling to give a low melting solid identifiedas ethyl 2- m-pyrrolidinylphenoxy) acetate.

Anal.Calc. for C l-I NO N, 5.6. Found N, 5.4.

Example IV Additional compounds were prepared in accordance with theprocedure of Examples I and II. The melting points of representativecompounds are listed in Table I:

TAB LE I Compound No.

Recrystallization Solvent (as listed above) Melting Point 0.)

.Aeetonltrile H *Taken on Fisher-Johns Melting Point Block andcorrected.

Example VI Additional compounds were prepared in accordance with theprocedure of Examples I and II and tested. The boiling points and/orrefractive indices of representative compounds are listed in Table II.

TAB LE II Compound No. Boiling Point, Pressure, an (as listed above) 0mm.

9999999999999999999999 CFO HOORO OHMON eeeeeeaaaweowwm g The compoundsof this invention can be used to reduce the cholesterol level of bloodeither directly or preferably by incorporating into a hypocholesteremiccomposition.

In addition to the heterocyclic amino phenoxyacetic acid compound, thehypocholesteremic compositions of the invention include a carrier whichcan be water, an organic solvent, or other diluent, a cream or emulsionbase of conventional formulation or a solid carrier such as is used inthe formulation of tablets and capsules. The compositions can beformulated so as to be administerable orally or parenterally. By suchmethods these compositions have the ability to markedly reduce thechloresterol level of blood in animals. The toxicity of these compoundsis quite low, and the active ingredient can be administered in dosagesadequate to obtain a therapeutic effect without adverse side effects.The concentration of the phenoxyacetic acid compound in thesecompositions is not in any way critical, but can be adjusted to meet theneed. In general, the concentration for oral and parenteraladministration will lie within about 1 to about 300 mg. per unit dosage,i.e., per cc. of solution or per tablet or capsule, depending upon thedosage regimen desired and the weight and hypocholesteremic state of theanimal. Ordinarily, it is preferable to administer a composition havinga low concentration of the active ingredient several times daily, ascompared to a single daily dose having a relatively high concentrationof the active ingredient, to achieve the total daily dosage required.The daily dosage is generally within the range of about to about 300 mg.of acid compound.

In the process of the invention, the heterocyclic amino phenoxyaceticacid compound or mixture thereof in an appropriate amount to obtain atherapeutic effect is administered to the patient orally, parenterallyor by any other appropriate method, and there results ahypocholesteremic response.

The examples illustrate various types of compositions coming within theinvention for a variety of administration techniques.

Example VII A composition of matter for oral administration, comprisingethyl o-(l-pyrrolidinyl) phenoxy acetate acid as the active ingredientin combination with a suitable carrier, was prepared by thoroughlymixing together 1000 grams of the active compound and 3500 grams ofbetalactose (milk sugar), passing the blended mixture through a No. 40screen and filling the mix into gelatin capsules, 450 mg. per capsule,each capsule to contain 100 mg. of active ingredient.

Example VIII A composition of matter for oral administration, in tabletform, comprising cyclohexyl (m-l-pyrrolidinyl) phenoxy isopropionate asthe active ingredient in combination with a suitable carrier, wasprepared by compounding the following ingredients into a tablet mix:

Grams Active ingredient 308 Sugar 308 Lactose 177 Starch 98 Dextrin 50Talcum 10 Stearic acid 10 Starch paste, q.s. to make 1000.

The above mix was compressed into tablets, weighing approximately 325mg., each table containing 100 mg. of active ingredient.

Example IX A composition of matter for parenteral administrationcomprising m-(l-pyrrolidinyl) phenoxy methylacetamide as the activeingredient in combination with a liquid carrier and having the followingformula was prepared:

Grams Active ingredient 25 Sodium hydroxide 5.74 Benzyl alcohol 5 Water,pyrogen-free, q.s. to 500 ml.

In making this solution the active ingredient was dissolved in 400 ml.of pyrogen-free water containing the sodium hydroxide, the benzylalcohol added, and the solution was made up q.s. to 500 ml.; after whichthe solution was filtered aseptically and filled aseptically in ampulescontaining 1 ml., under a nitrogen atmosphere. The resulting solutionsupplied a dosage unit of 50 mg. of active ingredient.

Compositions of matter similar to those described under Examples V, VIand VII may be made by including other substances having therapeuticproperties which enhance the total therapeutic value of the heterocyclicamino phenoxyacetic acid compound by their additive or by a synergisticeffect; the effect, if synergistic, will enhance the therapeutic valueof the heterocyclic amino phenoxyacetic compound without increase indosage. Thus, known therapeutic substances, such as aspirin orequivalent salicylate compound, may be added for their analgesic andanti-rheumatic effect butazolidin or antipyrine or related compounds fortheir anti-pyretic and anti-phlogistic effects, hydrocortisone orprednisolone or one of its equivalent corticosteroids for theiranti-rheumatic, anti-inflammatory and anti-phlogistic effects. Thecombination of a heterocyclic amino phenoxyacetic acid compound with oneor more of the above additive substances also serves the purpose of anadditive effect.

If desired, other substances, such as ascorbic acid, vitamin K,thiamine, etc., may be added to the composition of matter in adequatedosage to exert their individual activity for the therapeutic uses theyare known to have.

If desired, the hypocholesteremic compositions can be sterilized and cancontain auxiliary substances such as buffering agents, stabilizingagents, wetting agents and emulsifying agents.

To illustrate the therapeutic utility of the compounds of this inventionin reducing the cholesterol level of blood, normal adult guinea pigswere given subcutaneous doses corresponding to 30 mg./kg. of the testcompound at the beginning of the experiment, 24 hours later and finally,40 hours later.

Blood samples were drawn for the determination of serum cholesterollevels at the initiation of the experiment and at 48, and 72 hoursthereafter.

The hypocholesteremic response is Table III.

In this table, the compound is identified by its number in the listabove. The LD indicates the minimum dose which is lethal to mice whenthe compound is administered subcutaneously and is expressed in mg./kg.The dose is the dosage of the drug administered subcutaneously expressedmg./kg. under the schedule described above and the effect of thecompound in reducing cholesterol is indicated by the percent reductionfrom the cholesterol level noted for the animal at the initiation of theexperiment (percent hypocholesteremia).

Thus, if at the initiation of the experiment the noted cholesterol levelwas mg. percent and at a subsequent interval, the noted cholesterollevel was 60 mg. percent, this would be shown as 25% hypocholesteremia.

indicated in TABLE III.IIYPOCHOLESTEREMIC EFFECT OF REPRESENTATIVECOMPOUNDS Percent Hypocholestcremia Compound LDmin.,mg./kg.,

No. so.

48 hrs. 72 hrs.

It will be noted that certain of the compounds tested were fast actingwhile others showed a more sustained action or a delayed action. In manycases it is desirable to employ a mixture of several compounds to obtainboth rapid and sustained overall hypocholesteremic response.

It is evident from Table III that the compounds of this invention showsubstantial hypocholesteremic activity at dosage levels substantiallybelow the minimum lethal doses. A considerable reduction of cholesterollevels is obtained at substantially of the LD for many of the compounds.

Under clinical conditions the rapidity of the depression of cholesterollevels obtained in the tests reported above would not be required sothat even smaller doses could be used, thereby increasing the margin ofsafety.

The compounds of this invention in addition to their hypocholesteremicactivity are also useful intermediates in the production of othercompounds and also have utility as muscle relaxants andanti-inflammatory agents.

We claim:

1. A compound selected from the group consisting of those having theformula wherein R is selected from the group consisting of hydrogen andlower alkyl; N Z is selected from the group consisting of X-pyrrolidino,X-piperidino, X-hexamethyl- CIlCliH'llIlO, X-morpholino,X-thiomonpholino, X'octamethyleneimino, wherein X is selected from thegroup consisting of hydrogen, lower alkyl, hydroxy and acetyl; and R isselected from the group consisting of lower alkyl, cycloalkyl havingfrom five to seven carbon atoms and alkylamino of the formula wherein Rand R are selected vfrom the group consisting of hydrogen, lower alkyl,monoand di-(lower alkyl) amino-lower alkyl and amino-lower alkyl; andthe nontoxic acid addition salts and quaternary ammonium salts thereof.

2. A compound in accordance with claim 1, in which R is alkyl.

3. A compound in accordance with claim 1 wherein N Z is pyrrolidino.

4. A compound in accordance with claim 1 wherein N Z is piperidino.

No references cited.

HENRY R. JILES, Acting Primary Examiner. JOSE TOVAR, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULA